Context: In humans, few studies have compared the potencies of ergocalciferol and cholecalciferol in improving and maintaining vitamin D status. Objective: Our objective was to evaluate the effects of a single very large dose of both calciferols on serum changes of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)₂D], ionized calcium, and parathyroid hormone (PTH) at baseline, and at 3, 7, 30, and 60 d. Design: This was a prospective randomized intervention study. Setting: The study was performed in a nursing home residence. Participants: A total of 32 elderly female patients (age range 66–97 yr), with vitamin D deficiency was included in the study. Intervention: Participants were randomized into four groups of eight to receive a single dose of 300,000 IU ergocalciferol or cholecalciferol by oral (os) or im route. Results: 25(OH)D levels sharply increased at d 3 only when vitamins were given os. The 30-d basal difference in serum 25(OH)D was significantly greater after cholecalciferol os administration (47.8 ± 7.3 ng/ml) compared with other forms (D₃ im: 15.9 ± 11.3; D₂ os: 17.3 ± 4.7; D₂ im: 5 ± 4.4; all P < 0.001). The area under the curve (AUC) of the serum 25(OH)D against time (AUC₆₀) was: D₃ os, 3193 ± 759 ng × d/ml vs. D₂ os, 1820 ± 512, P < 0.001; and D₃ im, 1361 ± 492 vs. D₂ im, 728 ± 195, P < 0.01. 25(OH)D significantly influences PTH levels at 3 (P < 0.03), 7 (P < 0.01), 30 (P < 0.01), and 60 d (P < 0.05). At 60 d, the form of vitamin (cholecalciferol) significantly lowers PTH levels (P = 0.037). Conclusions: Cholecalciferol is almost twice as potent as ergocalciferol in increasing serum 25(OH)D, when administered either by mouth or im. 25(OH)D plays a role in modulating serum PTH.